Androgens functioning through the androgen receptor (AR) are required for survival of prostate epithelial cells and androgen deprivation is a common treatment for advanced prostate cancer. Androgen deprivation is successful in most cases. However, tumors often relapse and exhibit a hormone-independent phenotype where cancer cells are no longer dependent on androgens for survival. At this stage, therapeutic options are limited and most patients with androgen insensitive prostate cancer die from their disease. To improve treatment options for these patients, we need to understand the mechanisms by which the AR controls prostate cell apoptosis. The AR is a transcription factor and it has been thought that AR-induced gene expression is required for prostate epithelial cell survival. Conversely, it is hypothesized that removal of hormone results in loss of expression of these genes thus leading to prostate cell apoptosis. However, there are few convincing candidates for genes whose expression is AR-dependent and might be responsible for this effect. Recently, a quite different way for regulation of apoptosis by the AR was described. This mechanism involves proteolysis of the AR to release a toxic peptide. This mechanism is hormone-dependent because proteolysis does not occur in the presence of androgens. Our preliminary studies indicate that this mechanism can function in normal prostate epithelial cells. We hypothesize that this new mechanism contributes to androgen regulation of prostate cell survival and that defects in this mechanism may contribute to the progression of advanced prostate cancer. In this pilot project, we will test our hypothesis with the following aims: l) Identify toxic proteolytic fragments from the normal androgen receptor. 2) Determine the mechanism of androgen receptor proteolysis-induced cell death. The experiments proposed here will determine how this mechanism contributes to prostate epithelial cell survival and apoptosis. These studies may open a new avenue of research into androgen regulation of prostate cell survival and lead to novel therapeutic strategies to treat advanced prostate cancer.